1. Field of the Invention
The present invention is related generally to a treatment for systemic infections with yeast and mold organisms and specifically to a composition and method for parenteral administration of the general class of antiproliferative (antifungal) agents commonly referred to as azoles, and that contain itraconazole, posaconazole, voriconazole, fluconazole, ketoconazole and related compounds including, but not limited to mebendazole, in the treatment of such infections including, but not limited to fungal infections, that are sensitive to this general class of anti-infectious agents.
2. Description of Related Art
The antifungal azole agents itraconazole (ITZA) and posaconazole (POSA), that belong to the general class of agents commonly referred to as tri-azole compounds, have earned an impressive reputation for their efficacy against both yeast and various molds (Ref 1-28). The introduction of such azoles in clinical medicine has greatly improved the control of systemic fungal infections in both HIV- and non-HIV-infected immunocompromised individuals. These compounds are active against a variety of fungal infections such as aspergillosis, blastomycosis, histoplasmosis, and candidiasis, as well as fungal infections localized to the toenails and fingernails (onychomycosis), and to infections of the skin and reproductive tract (primarily referred to as “vaginal yeast infections”). They are also used for empirically and preemptively treating immunocompromised patients with fever and low white blood cell counts who are likely to develop a fungal infection after radio- or chemotherapy for malignant disease. For the purpose of this disclosure most of the data displayed and discussed will pertain to two members of the family only, since they have similar clinical shortcomings, namely itraconazole (ITZA) and posaconazole (POSA). They will be referred to collectively under the label of ITZA, unless otherwise specified.
DOSING: The usual recommended dose varies between the different members of the azole family in a single dose or two to three divided daily doses. Capsules should be taken with a full meal because lipid-containing food improves absorption.
ITZA and POSA are assumed to be rapidly absorbed from the intestinal tract. ITZA has an average bioavailability of approximately 50% while POSA has “variable” bioavailability depending on nutritional state, and a multitude of other factors that affect intestinal absorption (Ref 24, 29). Thus, intestinal absorption is highly variable, it is dependent on the intestinal microenvironment, on pH, the fat content of ingested food, and various other parameters that are only partly understood at this time (Ref 30). Unfortunately, detailed accurate data regarding intestinal absorption, as well as a thorough understanding of factors that determine this variable absorption are not available, neither are data regarding possible inter-individual variations in hepatic first-pass metabolism that further impact overall bioavailability. The impact of these factors cannot be assessed due to the absence of an IV reference formulation.
The poor solubility and physical instability of ITZA in aqueous solution has prevented the development of a useful parenteral ITZA formulation that could be used for routine clinical administration as well as for detailed pharmacological investigations. This lack of (a) solubilized IV preparation(s) impaired the development of optimal administration schedules, and it has therefore hampered the optimal clinical use of ITZA and its related analogs. Similarly, the available POSA formulation is limited to an oral suspension with a related spectrum of logistical problems that mirror those of ITZA, namely erratic and unpredictable intestinal absorption, that is dependent on intestinal pH and intestinal lipid content to allow optimal absorption, this is further compounded by varying degrees of hepatic first-pass extraction (24, 29. 30,).
Clinical frustration is mounting over the practical problems connected with these otherwise excellent antifungal agents; On one hand their broad antifungal spectrum has contributed to increasingly better control of established mold infections in immunocompromized patients and a decrease in clinically proven mold infections in high-risk patient populations when the compound(s) is/are used in a preemptive or “prophylactic” fashion, while on the other hand a lack of consistency in systemic exposure after oral dose delivery is troublesome, especially in the early treatment phase of a systemic fungal (especially mold-) infection, where it is of paramount importance to rapidly establish infection control.
Because of unreliable intestinal absorption, the use of oral antifungals is clearly suboptimal in many categories of immunodeficient patients, including those suffering from HIV-infections, in patients undergoing chemotherapy for malignant disease, and after hematopoietic stem cell transplantation where the occurrence of graft vs host disease may further impair intestinal function and therefore impede drug bioavailability. In such patients the delivery of concomitant medications that result in hypo- or achlorhydria, and/or diarrhea may also impact intestinal absorption of oral drugs. In addition, the ability to rapidly achieve therapeutic blood and tissue concentrations of antifungal agents in patients who have acquired opportunistic fungal infections is of crucial importance. For all of these reasons, the development of parenteral formulations of ITZA, POSA and later azole generations are highly desirable (Ref 31).
Based on a pharmacokinetic model that was developed from data in healthy volunteers who received single IV ITZA infusions followed by oral drug doses and subsequently validated in HIV-infected patients with opportunistic fungal infections it was concluded that an IV dosing regimen of ITZA given in a “loading phase” of 200 mg twice daily for 2 days, followed by once daily dosing of the same dose for another 5 days would produce ITZA concentrations similar to those achieved with oral ITZA given either as capsules for 28 days or as the oral solution for 14 days (Ref 32). These deliberations led to development of a microcrystalline ITZA suspension for IV administration that was introduced in clinical medicine and approved by the US FDA for use in patients with systemic fungal infections. However, due to stability issues this formulation was voluntarily removed by the supplier from the US market in early 2009.
The problems associated with oral administration of ITZA and POSA remain unchanged, and while the need for parenteral administration forms of these azoles clinically constitutes a highly desirable, unmet need. The solubility issues have hitherto prevented the development of parenterally acceptable formulations of both these azole analogs. Further, recent pharmacokinetic data obtained with both ITZA and POSA indicate, that (oral) administration with careful monitoring of plasma concentrations will improve the control of established fungal infections. Such findings should further encourage the development of parenteral solvent systems technology for dissolving and solubilizing the drugs, such that they can be administered in high-risk patients with high precision and complete dose assurance, yet without concern for hepatic first pass elimination and a continuous need for an established optimal nutritional state and intact intestinal function of the patients to facilitate the necessary reproducible intestinal absorption that will assure acceptable systemic drug bioavailability (Ref 31). Such parenteral administration forms would also allow a more thorough investigation of various administration schedules to further improve infection-control.
Previous approaches to increase solubility in poorly-soluble drugs include the addition of surfactants. US Patent Application No. 2009/0118354 describes a formulation to solubilize docetaxel using one or more non-ionic surfactants, more preferably polysorbate 80. Similarly, US Patent Application No. 2009/0253712 discloses an aqueous solvent system for azole antifungal agents requiring a surfactant, most preferably polysorbate 80. It has been established that surfactants have toxic effects to humans (Ref 33, 34, 35). Non-ionic surfactants can alter enzyme activity, irritate skin, and modify the permeability of blood cells (33). Cremophor ELTM (polyoxyethylated castor oil), a non-ionic surfactant, was found to cause anaphylactic hypersensitivity reactions, hyperlipidaemia, and neuotoxicity (36). Polysorbate 80 has also induced severe anaphylactic reactions (37). Therefore, the formulation of a solvent system that does not require the utilization of non-ionic surfactants is beneficial.
Given the toxicity of solubilizing agents such as non-ionic surfactants, previous approaches to increase solubility in poorly-soluble drugs have also included the addition of water as a means to dilute the toxic surfactants. See, for example, US Patent Application No. 2009/0253712, which describes a solvent system for azole antifungal agents, utilizes water in the solvent system (60-80% water by volume in the more preferred embodiment), which is stated to be for the purpose of diluting out the surfactant-associated toxicity (see, e.g., paragraph [0034]). However, azoles are highly lipophilic, and the presence of water can result in a thermodynamically unstable lipid emulsion and apparently reduce the stability of the drug. Furthermore, lipid emulsions are susceptible to aggregation, flocculation, and coalescence (38). If the homogeneity of the emulsion is significantly disrupted, the drug delivery is compromised. More importantly, a disrupted emulsion can cause serious adverse reactions including plasma-derived fat embolisms (39). Thus, in the interest of preserving and optimizing treatment safety for critically ill patients, there is a need to provide parenteral drug delivery systems that are both essentially free of non-ionic surfactants and have minimal water content.